This is a competing continuation application to identify and evaluate potential treatment medications for cocaine abuse and dependence in preclinical studies. Cocaine abuse is a significant public health problem and the development of effective anti-cocaine medications is a high priority for NIDA. The proposed interdisciplinary studies will involve pharmacology, medicinal chemistry, and behavioral science. The overall goal is to provide an empirical basis for translation of novel medication approaches into clinical treatment. The novel medications proposed for study are based on our discoveries during the past project period, and on recent findings from clinical studies. Agonist medications that mimic cocaine's interactions with the mesolimbic dopamine system may also produce selective and sustained decreases in the abuse-related effects of cocaine. However, the challenge is to identify long acting agonists with minimal abuse liability or other adverse side effects. We have found that two classes of compounds, non-selective monoamine releasers and mixed action mu/kappa agonists, each effectively reduce cocaine self-administration. We hypothesize that systematic manipulation of the relative ratio of dopamine to serotonin activity and the relative ratio of mu to kappa opioid activity may produce optimal monoaminergic and mixed action mu/kappa medications. We propose to study the effects of monoamine releasers, monoamine reuptake inhibitors and a novel stimulant, modafinil, as well as mu/kappa mixtures on cocaine self-administration and discrimination. Complementary behavioral procedures are proposed to provide a comprehensive evaluation of the effects of novel medications on the abuse-related effects of cocaine. Complete cocaine dose-effect curves will be studied in each procedure. Drug discrimination procedures will be used to characterize the potency, time course and cocaine-like stimulus characteristics of novel compounds. Medications will be administered chronically to model clinical treatment paradigms, and to determine the stability of treatment medication effects, the duration of any adverse side effects, and to monitor medication withdrawal signs when treatment is discontinued. The relative selectivity of medication effects will be determined in a Second Order Schedule of cocaine- and food- maintained responding. A Progressive Ratio procedure will be used to compare those treatment drugs that selectively reduce cocaine self-administration to determine the extent to which they alter the reinforcing efficacy of cocaine. This research will suggest new medication-based approaches to treatment of this serious and pervasive addictive disorder. PUBLIC HEALTH RELEVANCE: Cocaine abuse is a significant public health problem and the development of effective anti-cocaine medications is a high priority for NIDA. We propose interdisciplinary preclinical studies of two novel medication approaches to cocaine abuse treatment, based in part on our discoveries during the past project period. Medicinal chemist collaborators will synthesize mixed action mu/kappa medications and novel monoaminergic medications for this project. The effectiveness of these novel medications for reducing the abuse-related effects of cocaine will be evaluated in powerful drug self-administration and drug discrimination procedures that have excellent predictive validity for translation into clinical treatment.